tbuckley/cabot-search huggingface dataset:
In Situ Forming Hydrogel as a Tracer and Degradable Lacrimal Plug for Dry Eye Treatment
Authors: Mali Dai, Kejia Xu, Decheng Xiao, Yujing Zheng, Qinxiang Zheng, Jianliang Shen, Yuna Qian, Wei Chen
Journal: Advanced Healthcare Materials (2022)

Abstract Lacrimal plug is an effective and widely therapeutic strategy to treat dry eye. However, almost all commercialized plugs are fixed in a certain design and associated with many complications, such as spontaneous plug extrusion, epiphora, and granuloma and cannot be traced in the long‐term. Herein, a simple in situ forming hydrogel is developed as a tracer and degradable lacrimal plug to achieve the best match with the irregular lacrimal passages. In this strategy, methacrylate‐modified silk fibroin (SFMA) is served as a network, and a self‐assembled indocyanine green fluorescence tracer nanoparticle (FTN) is embedded as an indicator to develop the hydrogel plug using visible photo‐crosslinking. This SFMA/FTN hydrogel plug has excellent biocompatibility and biodegradability, which can be noninvasively monitored by near‐infrared light. In vivo tests based on dry eye rabbits show that the SFMA/FTN hydrogel plug can completely block the lacrimal passages and greatly improve the various clinical indicators of dry eye. These results demonstrate that the SFMA/FTN hydrogel is suitable as an injectable and degradable lacrimal plug with a long‐term tracking function. The work offers a new approach to the development of absorbable plugs for the treatment of dry eye.
The minimal active domain of human salivary histatin 1 is efficacious in promoting acute skin wound healing
Authors: Xiao-Xuan Lei, Liu Hang-Hang Cheng, Hai-Yan Lin, Yu Yang, Yun-Yu Lu, Meng-Ru Pang, Yun-Qing Dong, Floris J. Bikker, Tymour Forouzanfar, Biao Cheng, Gang Wu
Journal: Military Medical Research (2022)
A common IL‐4 receptor variant promotes asthma severity via a T<sub>reg</sub> cell GRB2‐IL‐6‐Notch4 circuit
Authors: Mehdi Benamar, Hani Harb, Qian Chen, Muyun Wang, Tsz Man Fion Chan, Jason Fong, Wanda Phipatanakul, Amparito Cunningham, Deniz Ertem, Carter R. Petty, Amirhosein J. Mousavi, Constantinos Sioutas, Elena Crestani, Talal A. Chatila
Journal: Allergy (2022)

Abstract Background The mechanisms by which genetic and environmental factors interact to promote asthma remain unclear. Both the IL‐4 receptor alpha chain R576 (IL‐4RαR576) variant and Notch4 license asthmatic lung inflammation by allergens and ambient pollutant particles by subverting lung regulatory T (T reg ) cells in an IL‐6‐dependent manner. Objective We examined the interaction between IL‐4RαR576 and Notch4 in promoting asthmatic inflammation. Methods Peripheral blood mononuclear cells (PBMCs) of asthmatics were analyzed for T helper type 2 cytokine production and Notch4 expression on T reg cells as a function of IL4R R576 allele. The capacity of IL‐4RαR576 to upregulate Notch4 expression on T reg cells to promote severe allergic airway inflammation was further analyzed in genetic mouse models. Results Asthmatics carrying the IL4R R576 allele had increased Notch4 expression on their circulating T reg cells as a function of disease severity and serum IL‐6. Mice harboring the Il4ra R576 allele exhibited increased Notch4‐dependent allergic airway inflammation that was inhibited upon T reg cell‐specific Notch4 deletion or treatment with an anti‐Notch4 antibody. Signaling via IL‐4RαR576 upregulated the expression in lung T reg cells of Notch4 and its downstream mediators Yap1 and beta‐catenin, leading to exacerbated lung inflammation. This upregulation was dependent on growth factor receptor‐bound protein 2 (GRB2) and IL‐6 receptor. Conclusion These results identify an IL‐4RαR576‐regulated GRB2‐IL‐6‐Notch4 circuit that promotes asthma severity by subverting lung T reg cell function.
Multisite implementation of a workflow-integrated machine learning system to optimize COVID-19 hospital admission decisions
Authors: Jeremiah S. Hinson, Eili Klein, Aria Smith, Matthew Toerper, Trushar Dungarani, David Hager, Peter Hill, Gabor Kelen, Joshua D. Niforatos, R. Scott Stephens, Alexandra T. Strauss, Scott Levin
Journal: npj Digital Medicine (2022)

Demand has outstripped healthcare supply during the coronavirus disease 2019 (COVID-19) pandemic. Emergency departments (EDs) are tasked with distinguishing patients who require hospital resources from those who may be safely discharged to the community. The novelty and high variability of COVID-19 have made these determinations challenging. In this study, we developed, implemented and evaluated an electronic health record (EHR) embedded clinical decision support (CDS) system that leverages machine learning (ML) to estimate short-term risk for clinical deterioration in patients with or under investigation for COVID-19. The system translates model-generated risk for critical care needs within 24 h and inpatient care needs within 72 h into rapidly interpretable COVID-19 Deterioration Risk Levels made viewable within ED clinician workflow. ML models were derived in a retrospective cohort of 21,452 ED patients who visited one of five ED study sites and were prospectively validated in 15,670 ED visits that occurred before (n = 4322) or after (n = 11,348) CDS implementation; model performance and numerous patient-oriented outcomes including in-hospital mortality were measured across study periods. Incidence of critical care needs within 24 h and inpatient care needs within 72 h were 10.7% and 22.5%, respectively and were similar across study periods. ML model performance was excellent under all conditions, with AUC ranging from 0.85 to 0.91 for prediction of critical care needs and 0.80-0.90 for inpatient care needs. Total mortality was unchanged across study periods but was reduced among high-risk patients after CDS implementation.
A Bioprinted Bruch's Membrane for Modeling Smoke‐Induced Retinal Pigment Epithelium Degeneration via Hybrid Membrane Printing Technology
Authors: Jongmin Kim, Jeong Sik Kong, Hyeonji Kim, Yeonggwon Jo, Dong‐Woo Cho, Jinah Jang
Journal: Advanced Healthcare Materials (2022)

Abstract The retinal pigment epithelium (RPE) not only forms the outer blood‐retinal barrier (oBRB) but also plays a multifunctional role in the ocular system. The loss of this epithelium leads to serious diseases resulting in vision impairment. No effective treatment is available for the repair of RPE damage. A functional in vitro RPE model that allows the recapitulation of oBRB‐related pathophysiological responses is lacking. Here, a hybrid membrane printing technology is developed to fabricate cellular monolayers on the basement membrane to mimic human Bruch's membrane (BM). Using this technology, in vitro oBRB model containing the RPE monolayer on the printed BM with stable mechanical properties and fibril diameter similar to that of natural BM is developed. Compared to traditional collagen bioink, BM‐based bioink significantly promotes RPE functions in vitro. Finally, smoking‐like conditions are exposed to the model to recapitulate the absorption of mainstream cigarette smoke which is known as one of the risk factors for the disease progression. RPE function is damaged due to oxidative stress. Furthermore, the versatility of the model as a drug‐testing platform is confirmed by the suppression of oxidative stress via antioxidants. This technology shows potential for fabricating a functional oBRB model that reflects patient conditions.
Depth of response and progression-free survival in chronic lymphocytic leukemia patients treated with ibrutinib
Authors: Audrey M. Sigmund, Ying Huang, Amy S. Ruppert, Kami Maddocks, Kerry A. Rogers, Samantha Jaglowski, Seema A. Bhat, Adam S. Kittai, Michael R. Grever, John C. Byrd, Jennifer A. Woyach
Journal: Leukemia (2022)
Maternal prenatal immunity, neonatal trained immunity, and early airway microbiota shape childhood asthma development
Authors: Avery DeVries, Kathryn McCauley, Douglas Fadrosh, Kei E. Fujimura, Debra A. Stern, Susan V. Lynch, Donata Vercelli
Journal: Allergy (2022)

The path to childhood asthma is thought to initiate in utero and be further promoted by postnatal exposures. However, the underlying mechanisms remain underexplored. We hypothesized that prenatal maternal immune dysfunction associated with increased childhood asthma risk (revealed by low IFN-γ:IL-13 secretion during the third trimester of pregnancy) alters neonatal immune training through epigenetic mechanisms and promotes early-life airway colonization by asthmagenic microbiota.
Crosstalk of organelles in Parkinson’s disease – MiT family transcription factors as central players in signaling pathways connecting mitochondria and lysosomes
Authors: Martin Lang, Peter P. Pramstaller, Irene Pichler
Journal: Molecular Neurodegeneration (2022)

Abstract Living organisms constantly need to adapt to their surrounding environment and have evolved sophisticated mechanisms to deal with stress. Mitochondria and lysosomes are central organelles in the response to energy and nutrient availability within a cell and act through interconnected mechanisms. However, when such processes become overwhelmed, it can lead to pathologies. Parkinson’s disease (PD) is a common neurodegenerative disorder (NDD) characterized by proteinaceous intracellular inclusions and progressive loss of dopaminergic neurons, which causes motor and non-motor symptoms. Genetic and environmental factors may contribute to the disease etiology. Mitochondrial dysfunction has long been recognized as a hallmark of PD pathogenesis, and several aspects of mitochondrial biology are impaired in PD patients and models. In addition, defects of the autophagy-lysosomal pathway have extensively been observed in cell and animal models as well as PD patients’ brains, where constitutive autophagy is indispensable for adaptation to stress and energy deficiency. Genetic and molecular studies have shown that the functions of mitochondria and lysosomal compartments are tightly linked and influence each other. Connections between these organelles are constituted among others by mitophagy, organellar dynamics and cellular signaling cascades, such as calcium (Ca 2+ ) and mTOR (mammalian target of rapamycin) signaling and the activation of transcription factors. Members of the Microphthalmia-associated transcription factor family (MiT), including MITF, TFE3 and TFEB, play a central role in regulating cellular homeostasis in response to metabolic pressure and are considered master regulators of lysosomal biogenesis. As such, they are part of the interconnection between mitochondria and lysosome functions and therefore represent attractive targets for therapeutic approaches against NDD, including PD. The activation of MiT transcription factors through genetic and pharmacological approaches have shown encouraging results at ameliorating PD-related phenotypes in in vitro and in vivo models. In this review, we summarize the relationship between mitochondrial and autophagy-lysosomal functions in the context of PD etiology and focus on the role of the MiT pathway and its potential as pharmacological target against PD.
Letter to the editor: the inflamed subclass predicts immunotherapy response – external validations
Authors: Binghua Li, Yajuan Cao, Yunzheng Li, Chunxiao Cheng, Decai YU
Journal: Gut (2022)

<h3>Background and Objectives</h3> Evidence regarding the safety and efficacy of messenger RNA (mRNA) vaccines in patients with myasthenia gravis (MG) after immunosuppressive therapies is scarce. Our aim is to determine whether the mRNA-1273 vaccine is safe and able to induce humoral and cellular responses in patients with MG. <h3>Methods</h3> We performed an observational, longitudinal, prospective study including 100 patients with MG of a referral center for MG in our country, conducted from April 2021 to November 2021 during the vaccination campaign. The mRNA-1273 vaccine was scheduled for all participants. Blood samples were collected before vaccination and 3 months after a second dose. Clinical changes in MG were measured using the MG activities of daily life score at baseline and 1 week after the first and second doses. A surveillance of all symptoms of coronavirus disease 2019 (COVID-19) was conducted throughout the study. Humoral and cellular immune responses after vaccination were assessed using a spike-antibody ELISA and interferon gamma release assay in plasma. The primary outcomes were clinically significant changes in MG symptoms after vaccination, adverse events (AEs), and seroconversion and T-cell immune response rates. <h3>Results</h3> Ninety-nine patients completed the full vaccination schedule, and 98 had 2 blood samples taken. A statistically significant worsening of symptoms was identified after the first and second doses of the mRNA-1273 vaccine, but this was not clinically relevant. Mild AEs occurred in 14 patients after the first dose and in 21 patients after the second dose. Eighty-seven patients developed a humoral response and 72 patients showed a T-cell response after vaccination. A combined therapy with prednisone and other immunosuppressive drugs correlated with a lower seroconversion ratio (OR = 5.97, 95% CI 1.46–24.09, <i>p</i> = 0.015) and a lower T-cell response ratio (OR = 2.83, 95% CI 1.13–7.13, <i>p</i> = 0.024). <h3>Discussion</h3> Our findings indicate that the mRNA vaccination against COVID-19 is safe in patients with MG and show no negative impact on the disease course. Patients achieved high humoral and cellular immune response levels. <h3>Classification of Evidence</h3> This study provides Class IV evidence that patients with MG receiving the mRNA-1273 vaccine did not show clinical worsening after vaccination and that most of the patients achieved high cellular or immune response levels.
LINE-1 promotes tumorigenicity and exacerbates tumor progression via stimulating metabolism reprogramming in non-small cell lung cancer
Authors: Zeguo Sun, Rui Zhang, Xiao Zhang, Yifei Sun, Pengpeng Liu, Nancy Francoeur, Lei Han, Wan Yee Lam, Zhengzi Yi, Robert Sebra, Martin Walsh, Jinpu Yu, Weijia Zhang
Journal: Molecular Cancer (2022)

Long Interspersed Nuclear Element-1 (LINE-1, L1) is increasingly regarded as a genetic risk for lung cancer. Transcriptionally active LINE-1 forms a L1-gene chimeric transcript (LCTs), through somatic L1 retrotransposition (LRT) or L1 antisense promoter (L1-ASP) activation, to play an oncogenic role in cancer progression.
Personalized diagnostic approach and indirect quantification of extravasation in human anaphylaxis
Authors: Emilio Nuñez‐Borque, Diana Betancor, Carlos Pastor‐Vargas, Sergio Fernández‐Bravo, Ariadna Martin‐Blazquez, Natalia Casado‐Navarro, David López‐Domínguez, Alicia Gómez‐López, Pablo Rodriguez del Rio, Paloma Tramón, Juan María Beitia, Carmen Moreno‐Aguilar, David González‐de‐Olano, María José Goikoetxea, María Dolores Ibáñez‐Sandín, José Julio Laguna, Javier Cuesta‐Herranz, Vanesa Esteban
Journal: Allergy (2022)

Abstract Background Anaphylaxis is the most acute and life‐threatening manifestation of allergic disorders. Currently, there is a need to improve its medical management and increase the understanding of its molecular mechanisms. This study aimed to quantify the extravasation underlying human anaphylactic reactions and propose new theragnostic approaches. Methods Molecular determinations were performed in paired serum samples obtained during the acute phase and at baseline from patients presenting with hypersensitivity reactions. These were classified according to their severity as Grades 1, 2 and 3, the two latter being considered anaphylaxis. Tryptase levels were measured by ImmunoCAP, and serum protein concentration was quantified by Bradford assay. Human serum albumin (HSA) and haemoglobin beta subunit (HBB) levels were determined by Western blot and polyacrylamide gel electrophoresis, respectively. Results A total of 150 patients were included in the study. Of them, 112 had experienced anaphylaxis (83 and 29 with Grade 2 and 3 reactions, respectively). Tryptase diagnostic efficiency substantially improved when considering patients' baseline values (33%–54%) instead of the acute value threshold (21%). Serum protein concentration and HSA significantly decreased in anaphylaxis ( p &lt; .0001). HSA levels dropped with the severity of the reaction (6% and 15% for Grade 2 and 3 reactions, respectively). Furthermore, HBB levels increased during the acute phase of all hypersensitivity reactions ( p &lt; .0001). Conclusions For the first time, the extravasation underlying human anaphylaxis has been evaluated based on the severity of the reaction using HSA and protein concentration measurements. Additionally, our findings propose new diagnostic and potential therapeutic approaches for this pathological event.
Self‐Propelling Nanomotors Integrated with Biofilm Microenvironment‐Activated NO Release to Accelerate Healing of Bacteria‐Infected Diabetic Wounds
Authors: Shuang Xie, Kun Huang, Jiawen Peng, Yuan Liu, Wenxiong Cao, Dandan Zhang, Xiaohong Li
Journal: Advanced Healthcare Materials (2022)

Diabetic foot ulcer (DFU) treatment is challenged by persistent bacterial infection and hyperglycemia-caused vascular dysplasia. Herein, self-propelled nanomotors are designed to achieve biofilm microenvironment (BME)-activated multistage release of NO for effective sterilization and subsequent angiogenesis promotion. CaO2 nanoparticles (NPs) are capped with PDA layers, followed by complexation with Fe2+ and surface grafting of cysteine-NO to obtain Janus Ca@PDAFe -CNO NPs. In response to low pH in BME, the decomposition of CaO2 cores generates O2 from one side of Janus NPs to propel biofilm penetration, and the released H2 O2 and Fe2+ produce •OH through Fenton reaction. The concurrent glutathione-triggered release of NO can be converted into reactive nitrogen species, which exhibit significantly higher bactericidal efficacy than those with only generation of •OH or NO. The slow release of NO for an extended time period promotes endothelial cell proliferation and migration. On Staphylococcus aureus-infected skin wounds of diabetic mice, NP treatment eliminates bacterial infections and significantly elevates blood vessel densities, leading to full wound recovery and regeneration of arranged collagen fibers and skin accessories. Thus, the self-propelling and multistage release of NO provide a feasible strategy to combat biofilm infection without using any antibiotics and accelerate angiogenesis and wound healing for DFU treatment.
Predictive factors and outcomes for ibrutinib in relapsed/refractory marginal zone lymphoma: a multicenter cohort study
Authors: Narendranath Epperla, Qiuhong Zhao, Sayan Mullick Chowdhury, Lauren Shea, Tamara K. Moyo, Nishitha Reddy, Julia Sheets, David M. Weiner, Praveen Ramakrishnan Geethakumari, Malathi Kandarpa, Ximena Jordan Bruno, Colin Thomas, Michael C. Churnetski, Andrew Hsu, Luke Zurbriggen, Cherie Tan, Kathryn Lindsey, Joseph Maakaron, Paolo F. Caimi, Pallawi Torka, Celeste Bello, Sabarish Ayyappan, Reem Karmali, Seo-Hyun Kim, Anna Kress, Shalin Kothari, Yazeed Sawalha, Beth Christian, Kevin A. David, Irl Brian Greenwell, Murali Janakiram, Vaishalee P. Kenkre, Adam J. Olszewski, Jonathon B. Cohen, Neil Palmisiano, Elvira Umyarova, Ryan A. Wilcox, Farrukh T. Awan, Juan Pablo Alderuccio, Stefan K. Barta, Natalie S. Grover, Nilanjan Ghosh, Nancy L. Bartlett, Alex F. Herrera, Geoffrey Shouse
Journal: Journal of Hematology & Oncology (2022)

Abstract Ibrutinib is effective in the treatment of relapsed/refractory (R/R) marginal zone lymphoma (MZL) with an overall response rate (ORR) of 48%. However, factors associated with response (or lack thereof) to ibrutinib in R/R MZL in clinical practice are largely unknown. To answer this question, we performed a multicenter (25 US centers) cohort study and divided the study population into three groups: “ibrutinib responders”—patients who achieved complete or partial response (CR/PR) to ibrutinib; “stable disease (SD)”; and “primary progressors (PP)”—patients with progression of disease as their best response to ibrutinib. One hundred and nineteen patients met the eligibility criteria with 58%/17% ORR/CR, 29% with SD, and 13% with PP. The median PFS and OS were 29 and 71.4 months, respectively, with no difference in PFS or OS based on the ibrutinib line of therapy or type of therapy before ibrutinib. Patients with complex cytogenetics had an inferior PFS (HR = 3.08, 95% CI 1.23–7.67, p = 0.02), while those with both complex cytogenetics (HR = 3.00, 95% CI 1.03–8.68, p = 0.04) and PP (HR = 13.94, 95% CI 5.17–37.62, p &lt; 0.001) had inferior OS. Only primary refractory disease to first-line therapy predicted a higher probability of PP to ibrutinib (RR = 3.77, 95% CI 1.15–12.33, p = 0.03). In this largest study to date evaluating outcomes of R/R MZL treated with ibrutinib, we show that patients with primary refractory disease and those with PP on ibrutinib are very high-risk subsets and need to be prioritized for experimental therapies.
Circular RNA circPOLR2A promotes clear cell renal cell carcinoma progression by facilitating the UBE3C-induced ubiquitination of PEBP1 and, thereby, activating the ERK signaling pathway
Authors: Zhipeng Xu, Shuqiu Chen, Ruiji Liu, Hui Chen, Bin Xu, Weizhang Xu, Ming Chen
Journal: Molecular Cancer (2022)

Increasing evidence has demonstrated that circular RNAs (circRNAs) are implicated in cancer progression. However, the aberrant expression and biological functions of circRNAs in clear cell renal cell carcinoma (cRCC) remain largely elusive.Differentially expressed circRNAs in cRCC were filtered via bioinformatics analysis. Aberrant circPOLR2A expression was validated in cRCC tissues and cell lines via qRT-PCR. Sanger sequencing was used to identify the backsplicing site of circPOLR2A. In vitro and in vivo functional experiments were performed to evaluate the role of circPOLR2A in cRCC malignancy. RNA pull-down, mass spectrometry, RIP, FISH and immunofluorescence assays were used to identify and validate the circPOLR2A-interacting proteins. Ubiquitination modification and interaction between proteins were detected via Co-IP and western blotting. The m6A modification in circPOLR2A was validated by the meRIP assay.Bioinformatics analysis revealed that circPOLR2A was highly expressed in cRCC tissues and metastatic cRCC tissues. CircPOLR2A expression was associated with tumor size and TNM stage in cRCC patients. In vitro and in vivo functional assays revealed that circPOLR2A accelerated cRCC cell proliferation, migration, invasion and angiogenesis, while inhibiting apoptosis. Further mechanistic research suggested that circPOLR2A could interact with UBE3C and PEBP1 proteins, and that UBE3C could act as a specific ubiquitin E3 ligase for the PEBP1 protein. The UBE3C/circPOLR2A/PEBP1 protein-RNA ternary complex enhanced the UBE3C-mediated ubiquitination and degradation of the PEBP1 protein which could inactivate the ERK signaling pathway. Rescue experiments revealed that the PEBP1 protein was the functional downstream target of circPOLR2A. Furthermore, m6A modification in circPOLR2A was confirmed, and the m6A reader YTHDF2 could regulate circPOLR2A expression.Our study demonstrated that circPOLR2A modulated the UBE3C-mediated ubiquitination and degradation of the PEBP1 protein, and further activated the ERK pathway during cRCC progression and metastasis. The m6A reader, YTHDF2, regulated circPOLR2A expression in cRCC. Hence, circPOLR2A could be a potential target for the diagnosis and treatment of cRCC.